This invention relates to pharmaceutical preparations and particularly to stable, cosmetically elegant topical preparations for the treatment of acne. This invention also includes a method of treatment of humans with the pharmaceutical preparations and ingredients to medicinally treat acne.
Acne is a common inflammatory disease in skin areas where sebaceous glands are largest, most numerous, and most active. In its mildest form, it is a more or less superficial disorder which is evidenced by slight, spotty skin irritations and ordinary skin hygiene is a satisfactory treatment. However, in the more inflammatory types of acne, bacterial invasion of or about the pilosebaceous follicle occurs and pustules, infected cysts, and in extreme cases canalizing inflamed and infected sacs appear. Without effective treatment, these lesions may become extensive and leave permanent, disfiguring scars.
Acne is very common in puberty. As reported by Hunnitz, S.: Clinical Pediatric Dermatology, p. 107 Philadelphia, W. B. Saunders Co., 1981, up to 85 percent of high school students have acne lesions and it is realistic to say that acne is so common 100 percent of persons between 9 and 19 have some experience with acne lesions. Usually by the early twenties the process of lesion formation slows considerably.
While acne is not a life-threatening disease, it may be cosmetically and emotionally disabling. The facial eruptions are known to cause psychic trauma. The sufferer may be constantly aware of the obvious facial blemishes. Thus, the immediate goals of treatment are to limit the physical and psychological scarring.
The etiology of lesion formation is viewed in the following way. The earliest acne lesions are comedones and are the result of the failure to normally slough the horny epidermal cells lining the follicular canal. Dilation of the orifice of a sebaceous follicle above a comedo will result in the extrusion of this mass at the surface resulting in an open comedo, a blackhead. If the pore above a comedo fails to dilate, then an impaction becomes a closed comedo or whitehead. The formation of a closed comedo can be followed by inflammatory lesions. Paules, pastules, modules and cysts may result from a process in which an impacted follicular sebaceous unit becomes the site of action of several products of Corynebacterium acnes, (P. Acnes) a normal anaerobic bacteria. Treatment of acne by a physician then becomes necessary.
Treatments that are currently used to treat acne include comedolytics, exfoliants, oral and topical bacteriostatics as well as systemic antibiotics. It is well known that the tetracycline antibiotics, and especially minocycline hydrochloride, are particularly effective in treating the condition when administered systemically. However, oral antibiotics can cause candidial vaginitis, photoreaction, onychlysis and gram-negative folliculitis, as well as headaches, dizziness and other central nervous system side effects.
Topical antibiotics offer the advantage of a decreased total absorption of the drug and an accompanying decrease in toxicity as compared with systemic antibiotics. Additionally, topical antibiotics offer the added benefit of applying the medication solely to the targeted lesions.
To reduce the severity of acne, a number of efforts have been made in the prior art to formulate topical preparations of the tetracycline antibiotics for use in acne therapy. However, these efforts have been hindered by the instability of the preparations in aqueous media. Tetracycline antibiotics are known to degrade rapidly with protic solvents to form epitetracycline, anhydrotetracycline, epianhydrotetracycline and other degradation products. These degradation products have negligible therapeutic activity. The degradation appears to start immediately upon solution and continues rapidly until an equilibrium is reached in the concentrations of tetracycline and epimer. This equilibrium point is temperature and pH dependent, with more epimer being formed at higher temperatures and lower pH. For example, at pH 4.2 and 3.degree. C. the ratio of minocycline:epimer is about 87:13; where as at pH 2.0 and 37.degree. C. the ratio of minocycline:epimer is 10:90. Even after this equilibrium is reached, degradation continues to take place due to oxidation and other side reactions. This leads to limited life for such tetracycline products in aqueous media.
To overcome the stability problem, the tetracycline antibiotics have been incorporated into various nonaqueous vehicles. Solutions of tetracycline antibiotics in alcohol based solvents are disclosed in U.S. Pat. Nos. 3,219,529, 3,389,174 and 4,376,118. However, the use of such alcohol based solvents have not been cosmetically acceptable due to irritation and drying of the skin. An aqueous ethanol solution of tetracycline hydrochloride in combination with an equilibrium concentration of the degradation product 4-epitetracycline hydrochloride has been commercially marketed under the trade name "Topicycline", but it is relatively unstable in its solution form due to continuous degradation. The product must be reconstituted from the powder prior to dispensing whereupon it is only stable for several months.
The tetracycline antibiotics have also been formulated in nonaqueous ointment bases, which are stable over a long period of time. While such formulations are desirable in that they are occlusive and they provide better penetration of the drug to the active site than a solution, their greasy consistency is particularly unacceptable in the treatment of acne. A formulation that is non-greasy such as a cream would be more acceptable, but most cream formulations are oil in water emulsions in which the tetracycline active ingredient is unstable.
Thus, there is a need for a topical tetracycline antibiotic preparation for the treatment of acne which is stable, provides good delivery of the drug to the skin surface, and yet is cosmetically acceptable for the purpose of acne therapy.